Health Council of the Netherlands

Tellurium

Evaluation of the effects on reproduction,recommendation for classification

2014/07

Tellurium2014/07

Health Council of the Netherlands

Tellurium

Evaluation of the effects on reproduction,

recommendation for classification

GezondheidsraadH e a l t h C o u n c i l o f t h e N e t h e r l a n d s

Aan de minister van Sociale Zaken en Werkgelegenheid

Onderwerp : Aanbieding advies Tellurium

Uw kenmerk : DGV/MBO/U-932542

Ons kenmerk : U-8075/HS/cn/543-H14

Bijlagen : 1

Datum : 3 april 2014

Geachte minister,

Graag bied ik u hierbij het advies aan over de effecten van tellurium op de vruchtbaarheid

en het nageslacht; het betreft ook effecten op de lactatie en via de moedermelk op

de zuigeling.

Dit advies maakt deel uit van een uitgebreide reeks waarin voor de voortplanting

giftige stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat

om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld.

Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad,

de Subcommissie Classificatie reproductietoxische stoffen. Het is vervolgens getoetst

door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.

Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van

Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.

Met vriendelijke groet,

prof. dr. W.A. van Gool,

voorzitter

B e z o e k a d r e s P o s t a d r e s

R i j n s t r a a t 5 0 P o s t b u s 1 6 0 5 2

2 5 1 5 X P D e n H a a g 2 5 0 0 B B D e n H a a g

E - m a i l : s . s t o u t e n @ g r . n l w w w . g r . n l

Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4

Tellurium

Evaluation of the effects on reproduction,

recommendation for classification

Subcommittee on the Classification of Reproduction Toxic Substances,

a Committee of the Health Council of the Netherlands

to:

the Minister of Social Affairs and Employment

No. 2014/07, The Hague, April 3, 2014

The Health Council of the Netherlands, established in 1902, is an independent

scientific advisory body. Its remit is “to advise the government and Parliament on

the current level of knowledge with respect to public health issues and health

(services) research...” (Section 22, Health Act).

The Health Council receives most requests for advice from the Ministers of

Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &

Employment, Economic Affairs, and Education, Culture & Science. The Council

can publish advisory reports on its own initiative. It usually does this in order to

ask attention for developments or trends that are thought to be relevant to

government policy.

Most Health Council reports are prepared by multidisciplinary committees of

Dutch or, sometimes, foreign experts, appointed in a personal capacity. The

reports are available to the public.

This report can be downloaded from www.healthcouncil.nl.

Preferred citation

Health Council of the Netherlands. Tellurium - Evaluation of the effects on

reproduction, recommendation for classification. The Hague: Health Council of

the Netherlands, 2014; publication no. 2014/07.

all rights reserved

ISBN: 978-90-5549-996-0

The Health Council of the Netherlands is a member of the European

Science Advisory Network for Health (EuSANH), a network of science

advisory bodies in Europe.

Contents

Samenvatting 9

Executive summary 11

1 Scope 13

1.1 Background 13

1.2 Committee and procedure 13

1.3 Labelling for lactation 14

1.4 Data 15

1.5 Presentation of conclusions 15

1.6 Final remark 16

2 Tellurium 17

2.1 Introduction 17

2.2 Human studies 18

2.3 Animal studies 19

2.4 Conclusions 24

References 27

Contents 7

Annexes 29

A The Committee 31

B The submission letter (in English) 33

C Comments on the public draft 35

D Regulation (EC) 1272/2008 of the European Community 37

E Additional considerations to Regulation (EC) 1272/2008 49

F Developmental toxicity studies 51

8 Tellurium

Samenvatting

In het voorliggende advies heeft de Gezondheidsraad tellurium onder de loep

genomen. Tellurium wordt gebruikt als additief in koper, ijzer en staal, in

gevulcaniseerd rubber, als pigment in glas en keramiek, en in sommige andere

applicaties. Dit advies past in een reeks adviezen waarin de Gezondheidsraad op

verzoek van de minister van Sociale Zaken en Werkgelegenheid de effecten van

stoffen op de voortplanting beoordeelt. Het gaat vooral om stoffen waaraan

mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De

Subcommissie Classificatie reproductietoxische stoffen van de Commissie

Gezondheid en beroepsmatige blootstelling aan stoffen van de raad, hierna

aangeduid als de commissie, kijkt zowel naar effecten op de vruchtbaarheid van

mannen en vrouwen als naar effecten op de ontwikkeling van het nageslacht.

Daarnaast worden effecten op de lactatie en via de moedermelk op de zuigeling

beoordeeld.

Op basis van Verordening (EG) 1272/2008 van de Europese Unie doet de

commissie een voorstel voor classificatie. Voor tellurium komt de commissie tot

de volgende aanbevelingen:

• voor effecten op de fertiliteit adviseert de commissie om tellurium niet te

classificeren wegens onvoldoende geschikte gegevens

• voor effecten op de ontwikkeling adviseert de commissie tellurium te

classificeren in categorie 1B (stoffen waarvan verondersteld wordt dat zij

Samenvatting 9

toxisch zijn voor de menselijke voortplanting) en te kenmerken met H360D

(kan het ongeboren kind schaden)

• voor effecten tijdens of via lactatie adviseert de commissie om tellurium niet

te kenmerken wegens onvoldoende geschikte gegevens.

10 Tellurium

Executive summary

In the present report, the Health Council of the Netherlands reviewed tellurium.

Tellurium is used as an additive to copper, iron and steel, in vulcanized rubber, as

a colouring agent in glass and ceramics, and in some other applications. This

report is part of a series, in which the Health Council evaluates the effects of

substances on reproduction, at request of the Minister of Social Affairs and

Employment. It mainly concerns substances to which man can be occupationally

exposed. The Subcommittee on the Classification of Reproduction Toxic

Substances of the Dutch Expert Committee on Occupational Safety of the Health

Council, hereafter called the Committee, evaluates the effects on male and

female fertility and on the development of the progeny. Furthermore, the

Committee considers the effects of a substance on lactation and on the progeny

via lactation.

The Committee recommends classification according to Regulation (EC) 1272/

2008 of the European Union. For tellurium, these recommendations are:

• for effects on fertility, the Committee recommends not classifying tellurium

due to a lack of appropriate data

• for effects on development, the Committee recommends classifying tellurium

in category 1B (presumed human reproductive toxicant) and labelling with

H360D (may damage the unborn child)

• for effects on or via lactation, the Committee recommends not labelling

tellurium due to a lack of appropriate data.

Executive summary 11

12 Tellurium

1Chapter

Scope

1.1 Background

As a result of the Dutch regulation on registration of compounds toxic to

reproduction that came into force on 1 April 1995, the Minister of Social Affairs

and Employment requested the Health Council of the Netherlands to classify

compounds toxic to reproduction. This classification is performed by the Health

Council's Subcommittee on the Classification of Reproduction Toxic Substances

of the Dutch Expert Committee on Occupational Safety (DECOS). The

classification is performed according to European Union Regulation (EC) 1272/

2008 on classification, labelling and packaging (CLP) of substances and

mixtures. The CLP guideline is based on the Globally Harmonised System of

Classification and Labelling of Chemicals (GHS). The Subcommittee's advice on

the classification will be applied by the Ministry of Social Affairs and

Employment to extend the existing list of compounds classified as reproductive

toxicant (category 1A, 1B or 2) and compounds with effects on or via lactation.

1.2 Committee and procedure

This present document contains the classification of tellurium by the Health

Council's Subcommittee on the Classification of Reproduction Toxic Substances,

hereafter called the Committee. The members of the Committee are listed in

Scope 13

Annex A. The submission letter (in English) to the Minister can be found in

Annex B.

In 2013, the President of the Health Council released a draft of the report for

public review. The individuals and organizations that commented on the draft

report are listed in Annex C. The Committee has taken these comments into

account in deciding on the final version of the report.

The classification is based on the evaluation of published human and animal

studies concerning adverse effects with respect to fertility and development and

lactation of the above-mentioned compound.

The classification and labelling of substances is performed according to the

guidelines of the European Union (Regulation (EC) 1272/2008) presented in

Annex D. The classification of compounds is ultimately dependent on an

integrated assessment of the nature of all parental and developmental effects

observed, their specificity and adversity and the dosages at which the various

effects occur. The guideline necessarily leaves room for interpretation, dependent

on the specific data set under consideration. In the process of using the

regulation, the Committee has agreed upon a number of additional considerations

(see Annex E).

1.3 Labelling for lactation

The recommendation for classifying substances for effects on or via lactation is

also based on Regulation (EC) 1272/2008. The guideline defines that substances

which are absorbed by women and have been shown to interfere with lactation or

which may be present (including metabolites) in breast milk in amounts

sufficient to cause concern for the health of a breastfed child, shall be classified

and labelled. Unlike the classification of substances for fertility and

Classification for reproduction (fertility (F) and development (D)):

Category 1 Known or presumed human reproductive toxicant (H360(F/D))

Category 1A Known human reproductive toxicant

Category 1B Presumed human reproductive toxicant

Category 2 Suspected human reproductive toxicant (H361(f/d))

No classification for effects on fertility or development

Classification for lactation:

Effects on or via lactation (H362)

No labelling for lactation

14 Tellurium

developmental effects, which is based on hazard identification only (largely

independent of dosage), the labelling for effects on or via lactation is based on a

risk characterization and therefore, it also includes consideration of the level of

exposure of the breastfed child.

Consequently, a substance should be labelled for effects on or via lactation

when it is likely that the substance would be present in breast milk at potentially

toxic levels. The Committee considers a concentration of a compound as

potentially toxic to the breastfed child when this concentration exceeds the

exposure limit for the general population, e.g. the acceptable daily intake (ADI).

1.4 Data

For the present evaluation, a review on the toxic effects of tellurium and

tellurium compounds by the Health Council’s Committee on Updating of

Occupational Exposure Limits was available.9 The last reference concerning

reproduction toxic effects cited in there was from 1988. Literature searches were

conducted in the online databases XTOXLINE, MEDLINE and CAPLUS, from

1988 up to February 2011. A final search was performed in TOXNET/TOXLINE

in November 2012. Literature was selected primarily on the basis of the text of

the abstracts. Publications cited in the selected articles, but not selected during

the primary search, were reviewed if considered appropriate. References are

divided into literature cited and literature consulted but not cited.

The Committee describes both the human and animal studies in the text. The

animal data are described in more detail in Annex F as well. Of each study the

quality of the study design (performed according to internationally

acknowledged guidelines) and the quality of documentation are considered.

1.5 Presentation of conclusions

The classification is given with key effects, species and references specified. In

case a substance is not classified as toxic to reproduction, one of two reasons is

given:

• lack of appropriate data precludes assessment of the compound for

reproductive toxicity

• sufficient data show that no classification for toxic to reproduction is

indicated.

Scope 15

1.6 Final remark

The classification of compounds is based on hazard evaluation only (Niesink et

al., 1995)16, which is one of a series of elements guiding the risk evaluation

process. The Committee emphasizes that for derivation of health-based

occupational exposure limits these classifications should be placed in a wider

context. For a comprehensive risk evaluation, hazard evaluation should be

combined with dose-response assessment, human risk characterization, human

exposure assessment and recommendations of other organizations.

16 Tellurium

2Chapter

Tellurium

2.1 Introduction

The identity and some physicochemical properties of tellurium are given below:

name : tellurium

CAS registry number : 13494-80-9

EC/EINECS number : 236-813-4

synonyms : aurum paradoxum; metallum problematum; telloy

colour and physical state : grey-white lustrous, brittle, crystalline solid, hexagonal,

rhombohedral structure; or dark-grey to brown, amorphous

powder with metal characteristics

formula : Te

atomic weight : 127.6

melting point : 449.5-449.8 °C

boiling point : 988-989.9 °C

vapour pressure : 130 Pa at 520 °C

density : 6.11-6.27 (crystalline)

solubility : insoluble in water

Tellurium 17

data from 3,9 unless otherwise noted.

So far, 39 tellurium isotopes with atomic masses ranging from 105 to 143 have

been discovered; these include eight stable, 16 neutron-deficient and 15 neutron-

rich isotopes.12 Tellurium is a heavy element with chemical properties

resembling those of non-metals, such as sulphur, but with more metal-like

physical properties. Regarding properties and toxicology, it is similar to

selenium, but tellurium is not considered to be a trace element. Biological

functions are not yet identified.15

The daily intake of tellurium for man was in the 1960s initially estimated to

be 600 µg but revised to 100 µg8; based on a more recent study, an intake

between 1 and 10 µg might be more realistic14. ‘Background’ concentrations of

tellurium in blood, saliva and urine are

Developmental toxicity studies

No data are available regarding the effects of exposure to tellurium on

development in humans.

Lactation

No data are available regarding the excretion of tellurium in breast milk or the

effects of exposure to tellurium on infants during the lactation period.

2.3 Animal studies

Fertility studies

No laboratory animal data are available regarding the effects of exposure to

tellurium on fertility.

Developmental toxicity studies

Developmental toxicity studies with tellurium in laboratory animals are

summarized in Annex F.

Oral studies

Garro and Pentschew (1964) fed more than 100 pregnant Long-Evans rats diets

containing 500, 1,250 or 2,500 ppm of metallic tellurium (based on the data of

Duckett and Johnson et al. (see below), these doses could be equal to 30, 75 and

150 mg/kg bw/day). Dams of the two lower dose groups were treated throughout

gestation while the high-dose animals were put on a normal diet three to five

days before the expected delivery to avoid abortions.

The newborn pups appeared normal although smaller than the controls.

Hydrocephalus, that developed immediately after birth, was found in 60-90%

and 100% of the pups of the mid- and high-dose groups, respectively, and in a

lower, unspecified percentage at the low dose. In all dose groups, 99% of the

affected pups died within one month.

Garro and Pentschew stated that the amounts administered were not toxic to

the dams tolerating the diets well and behaving normally.6

Tellurium 19

Agnew et al. (1968) found no hydrocephalus in the offspring of Wistar rats (n=4/

group) administered dietary amounts of 1,250 and 2,500 ppm of metallic

tellurium throughout gestation (based on the data of Duckett and Johnson et al.

(see below), these doses could be equal to 75 and 150 mg/kg bw/day).

When given 3,300 ppm (n=10) (approximately 200 mg/kg bw, see afore),

hydrocephalus, generally not grossly obvious until postnatal day 4 or 5, was seen

in 8/10 litters (allowed to live 19 days or longer after birth) and in 36/77 pups.

Data on maternal toxicity were not presented.1

Duckett (1970) fed Wistar rats (n=20/group) 0 or 3,000 ppm (about 180 mg/kg

bw/day*) of elemental tellurium in the diet on every gestational day (not further

specified). On gestational day 13 and 15, foetuses (number not specified) were

removed via the abdominal wall and after closing the abdominal wall again

animals were allowed to terminate their pregnancy and give birth. Only the

foetuses of tellurium-fed animals, which eventually gave birth to hydrocephalic

animals, and foetuses of similar age from the control rats were examined and

reported.

The size and appearance of the tellurium and control foetuses were similar.

No anomalies were noted in sections of the brains of the tellurium foetuses,

stained with haematoxylin-eosin. Electron microscopic examination showed

morphological anomalies in the cells in the ependymal layer of the tellurium

foetuses, 13- and 15-intrauterine-days old. The ependymal layer of the normal

foetal rat resembled that of human, rabbit and chick foetuses. On the ventricular

surface of the ependymal cells from tellurium foetuses the normally present

microvilli were not present and the number of mitochondria was greatly

diminished. Mitochondria were often abnormal, smaller and darker than normal

and showed distortion of cristae. The cells in the rest of the telencephalon

appeared to be normal.

No data on dams or pups were reported. Duckett only stated that from his

experience, the dose given resulted in 50% of the rats giving birth to litters

whose every member was hydrocephalic.4

Duckett et al. (1971) investigated in a later study the effect of periodical or single

dietary dosing on the occurrence of hydrocephalus. Pregnant rats (strain not

reported) were given 2,500 ppm (about 150 mg/kg bw/day using a body weight

of 250 g) of metallic tellurium in the diet for every gestational day (21 days) and

* Calculated based on 15 g food intake per day containing 45 mg of elemental tellurium and an average

body weight of 250 g at the beginning of pregnancy as indicated in Duckett (1970).

20 Tellurium

12/20 rats gave birth to litters containing an average of eight pups, six of which

were hydrocephalic. Subsequently, the same dose was given to three groups of

pregnant rats (n=20/group): the first group received tellurium from gestational

day 1 through 9, the second group on gestational day 10-15 and the third group on

day 16-21.

Twelve rats fed tellurium during gestational day 10-15 gave birth to

hydrocephalic rats. The average litter numbered nine, five of which were

hydrocephalic. No hydrocephalic pups were noted in the other two dose groups.

Also, single doses on one gestational day were given to five rats per group per

gestational day. Seventy-two animals gave birth to an average of eight offspring.

No hydrocephalic pups were noted.5

The Committee notes that the exact day of postnatal examination, the

absence or presence of maternal toxicity and statistics were not reported.

Johnson and co-workers (1988) performed a standard developmental toxicity

study in rats and rabbits generally performed according to OECD Test Guideline

414 (1981). Preliminary studies in the rat showed that gavage studies gave only

developmental toxicity at doses ≥10,000 mg/kg bw/day while dietary intake

resulted in effects at ≥559 mg/kg bw/day*. For the main studies, dietary

administration was chosen.

Pregnant Sprague-Dawley rats (n=32-33) were given 0, 30, 300, 3,000 or

15,000 ppm of tellurium in the diet on gestational day 6-15 (equal to

approximately 0, 2, 20, 166 and 633 mg/kg bw/day for gestational day 6-10 and

0, 2, 18, 173 and 580 mg/kg bw/day for gestational day 11-15**). On day 20 of

presumed gestation, approximately two-thirds of the females in each group were

killed and foetuses were investigated. The remaining dams in each group were

allowed to deliver and pups were observed until postnatal day 7. Heads of pups

which were stillborn, found dead or killed on postnatal day 7 were examined.

No effect was observed on the incidences of pregnancy, on the mean numbers

of corpora lutea, implantations and resorptions, on the mean litter size, on the

numbers of live and dead foetuses and on the percentages of male foetuses.

At 15,000 ppm, mean weights of female and male foetuses were decreased

(p≤0.05). Increased incidences of litters with variations (100%, controls: 18%;

p≤0.01) and of foetuses with variations (41%, controls: 2.1%; p-value not

reported), of malformed foetuses (no details presented), and of foetuses with

delayed ossification (no details presented) were reported. The most common

* Corresponds to 7,500 ppm Te in the diet as reported in Johnson et al.

** Calculated by Johnson et al. based on quantities of feed consumed.

Tellurium 21

malformation was internal hydrocephalus with dilatation of the lateral ventricles

observed in 17 litters (85%; controls: 1 (4.6%); p≤0.05) and in 67 foetuses

(55%; controls: 1 ( 0.7%); p≤0.05). More severely affected foetuses had also

slight to marked dilatation of the third and/or fourth ventricles. Externally,

hydrocephalus was noted only for two foetuses (litters not specified), one of

which had an enlarged fontanel bordered by a haemorrhagic area. Moderate

dilatation of the renal pelvis was also found (no details). Other malformations

included kinked and/or stubbed tails, rotation of a hindlimb or hind foot, a

malformed retina, malpositioned manubrium and clavicles, short radius, ulna

and/or femur, wavy ribs and a thickened or split rib. Many of these foetuses from

severely affected dams also showed delayed ossification of the parietals,

interparietals, supraoccipitals, vertebral and sternal centra, pubes, ischia and/or

ribs. At 3000 ppm, incidences of litters with variations (57%, p≤0.01) and of

foetuses with variations (11%, p-value not reported), of malformed foetuses (no

details presented) and of foetuses with delayed ossification (no details presented)

were increased as well. Also in this group, the most common malformation was

internal hydrocephalus with dilatation of the lateral ventricles observed in three

litters (14%; not statistically significant from controls) and in 11 foetuses (55%;

not statistically significant). Moderate dilatation of the renal pelvis was also

found (no details). No other malformations were observed.

Regarding the groups that were allowed to litter, there were no effects on

duration of gestation, on the number (percentage) of dams with stillborn, on litter

size, on the number of live pups delivered and on mean pup weights on postnatal

day 7. In the highest dose group, the number (percentage) of pups surviving

seven days was decreased (p≤0.01). No gross, external or visceral anomalies

were seen, but there was a significant increase in the incidence of slight to

extreme dilatation of the lateral ventricles in pups at the highest dose at postnatal

day 7 (p≤0.01).

No maternal mortality occurred. Maternal body weight gain and food

consumption were decreased at 300 and 3,000 ppm (p≤0.01), while weight loss

and halved food consumption were seen at 15,000 ppm (p≤0.01) during

exposure.11

In the same study, New Zealand white rabbits (n=17) were artificially

inseminated and fed diets containing 0, 17.5, 175, 1750 or 5,250 ppm of

tellurium (equal to approximately 0, 0.8, 8, 52, 97 mg/kg bw/day using average

feed intake on gestational days 6-18 and average maternal body weight on

gestational day 6) on gestational days 6-18. Dams were killed on gestational day

29 and foetuses were examined.

22 Tellurium

The number of pregnancies varied between dose levels: 10, 15, 9, 15 and 13

at 0, 17.5, 175, 1,750 and 5,250 ppm, respectively. No effect was observed on the

incidence of abortion, mean numbers of corpora lutea, implantations,

resorptions, litter size or sex ratio (% of male foetuses/litter). At 5,250 ppm,

decreased mean foetal weight (males 84%, females 95% of control; not

statistically significant), increased incidences of litters with abnormalities (46%;

controls: 2%) of foetuses with abnormalities (12%; controls: 6.7%), malformed

foetuses (no details presented) and foetuses with delayed ossification (no details

presented) were observed (no statistics reported). In the foetuses of this group,

the following effects were reported: low incidences of hydrocephalus; enlarged

and/or irregularly shaped anterior fontanel; incomplete ossification of, or small

holes in, the frontals and parietals; frontals with thickened ossification; umbilical

hernia; fused pulmonary artery and aorta; asymmetric and/or irregularly shaped

and/or fused sternebrae; and thickened areas in the ribs. These foetuses also

tended to be smaller than normal and had fewer caudal vertebral, xiphoid and

forepaw phalangeal foetal ossification sites.

Maternal toxicity consisted of soft or liquid faeces, alopecia, thin appearance,

and/or decreased motor activity and decreased body weight gain and food

consumption at 1,750 and 5,250 ppm (body weight gain: p≤0.01 at both doses;

food consumption: p≤0.05 at 1,750 and p≤0.01 at 5,250 ppm). 11

Intramuscular injection

In a subsequent study (see diet studies above), Agnew and Curry (1972)

investigated the precise period of teratogenic susceptibility of the rat embryo to

tellurium. Pregnant rats (n=5-10/experiment) were injected intramuscularly with

13 mg/kg bw metallic tellurium suspended in olive oil on one day of gestational

day 7 to 13; two or three pregnant controls were injected with single doses of

olive oil from gestational days 9-13. Dams were allowed to deliver and offspring

was observed for ten postnatal days, killed and examined for hydrocephalus and

other visceral defects. Only those mothers failing to deliver were autopsied and

examined for foetal resorptions the day following predicted delivery.

Apart from foetuses with hydrocephalus observed after injection on

gestational day 7 (1/31, 3%), 9 (14/75, 19%) and 10 (10/32, 31%) (controls:

1/94, 1%), no biologically relevant effects were noted. Malformations other than

hydrocephalus were not observed.

Data on maternal toxicity were not presented.2

Tellurium 23

Lactation

Two female rats were given a diet containing 0 or 1.25% of metallic tellurium

(about 750 mg/kg bw/day*) from postnatal day 0 until sacrifice at postnatal days

7, 14, 21 or 28 (n=5 pups/group). Apart from a garlic odour and skin

discoloration, no signs of toxicity were seen in the lactating dams. During the

postnatal period, neonates from treated mothers showed effects such as garlic

odour, skin discoloration, lethargy, hindlimb paralysis, incontinence, slow weight

gain and smaller size. Microscopic examination of nerve tissues revealed

hypomyelation, myelin degeneration, and Schwann cell degeneration.10

The Committee notes the limited study design.

2.4 Conclusions

Fertility

No human or animal studies on fertility effects of tellurium were available.

Therefore, the Committee proposes not to classify tellurium for effects on

fertility due to a lack of appropriate human and animal data.

Developmental toxicity

No human studies on developmental toxicity effects of tellurium were available.

In one developmental toxicity study, maternally toxic levels of tellurium

in the diet induced increased numbers of rat foetuses with dilated ventricles/

hydrocephalus, of rat foetuses with hydrocephalus and decreased weights and of

rabbit foetuses with variations and malformations and delayed ossification.11 In

other less well performed and reported diet studies in rats, tellurium caused

increased numbers of rat pups with hydrocephalus.1,4-6 In one of the latter

studies6, levels affecting the offspring were stated to be not toxic to the dams

while in the other studies1,4,5, it was not reported whether effects were seen in the

presence or absence of maternal toxicity.

The Committee is of the opinion that the developmental effects observed

occurred independently from maternal toxicity. Therefore, based on the data

from laboratory animal studies, the Committee recommends classification of

tellurium in category 1B (presumed human reproductive toxicant).

* Based on the data of Duckett and Johnson et al. (see afore).

24 Tellurium

Lactation

No human data and only limited animal data were available regarding the

excretion of tellurium in breast milk or the effects of exposure to tellurium on

infants during the lactation period.

Therefore, the Committee concluded that a lack of appropriate data

precludes assessment of tellurium for effects on or via lactation.

Proposed classification for fertility

Lack of appropriate data precludes the assessment of tellurium for effects on

fertility.

Proposed classification for developmental toxicity

Category 1B; H360D.

Proposed labelling for effects on or via lactation

Lack of appropriate data precludes the assessment of tellurium for effects on or

via lactation.

Tellurium 25

26 Tellurium

References

1 Agnew WF, Fauvre FM, Pudenz PH. Tellurium hydrocephalus: distribution of tellurium-127m

between maternal, fetal, and neonatal tissue of the rat. Exp Neurol. 1968;21:120-2.

2 Agnew WF, Curry E. Period of teratogenic vulnerability of rat embryo to induction of hydrocephalus

by tellurium. Experientia. 1972;28:1444-5.

3 Budavari S, O’Neil M, Smith A, Heckelman P, Obenchain J, editors. Tellurium. In: The Merck Index;

an encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station NJ, USA: Merck & Co,

Inc.; 1996.

4 Duckett S. Fetal encephalopathy following ingestion of tellurium. Experientia. 1970;26:1239-41.

5 Duckett S, Sandler A, Scott T. The target period during fetal life for the production of tellurium

hydrocephalus. Experientia. 1971;27:1064-5.

6 Garro F, Pentschew A. Neonatal hydrocephalus in the offspring of rats fed during pregnancy non-

toxic amounts of tellurium. Arch Psychiatr Zeitschr Neurol. 1964; 206:272-80.

7 George MW. Tellurium. [Internet]. [cited 2012 April]. Available from: http://minerals.usgs.gov/

minerals/pubs/commodity/selenium/mcs-2012-tellu.pdf.

8 Gerhardsson L. Tellurium. In: Nordberg GF, Fouler BA, Nordberg M, Friberg LT, editors. Handbook

of the toxicology of metals. Burlington MA, USA: Academic Press; 2007. p. 815-25.

9 Health Council of the Netherlands: Committee on Updating of Occupational Exposure Limits.

Tellurium and tellurium compounds (excluding TeF6). Health-based reassessment of administrative

occupational exposure limits. The Hague: Health Council of The Netherlands; 2002:

2000/15OSH/055.

10 Jackson KF, Hammang JP, Worth SF, Duncan ID. Hypomyelation in the neonatal rat central and

peripheral nervous system following tellurium intoxication. Acta Neuropathol. 1989;78:301-9.

References 27

11 Johnson EM, Christian MS, Hoberman AM, DeMarco CJ, Kilpper R, Mermelstein R. Developmental

toxicology investigation of tellurium. Fundam Appl Toxicol. 1988;11: 691-702.

12 Kathawa J, Fry C, Thoennessen M. Discovery of palladium, antimony, tellurium, iodine, and xenon

isotopes. At Data Nucl Data Tables. 2013;99:22-52.

13 Kron T, Hansen C, Werner E. Renal excretion of tellurium after peroral administration of tellurium in

different forms to healthy volunteers. J Trace Elem Electrolytes Health Dis. 1991;5:239-44.

14 Kron T, Hansen C, Werner E. Tellurium ingestion with foodstuffs. J Food Comp Anal. 1991;4:

196-205.

15 Larner AJ. Biological effects of tellurium: a review. Trace Elem Electrolytes. 1995;12:26-31.

16 Niessink R, de Vries J, Hoolinger M. Toxicology principles and applications. Boca Raton FL, USA:

CRC Press; 1995.

Literature consulted but not cited

- Barlow SM, Sullivan FM. Tellurium and its compounds. In: Reproductive hazards of industrial

chemicals: an evaluation of animal and human data. New York, USA: Academic Press; 1982.

p. 515-22.

28 Tellurium

A The Committee

B The submission letter (in English)

C Comments on the public draft

D Regulation (EC) 1272/2008 of the European Community

E Additional considerations to Regulation (EC) 1272/2008

F Developmental toxicity studies

Annexes

29

30 Tellurium

AAnnex

The Committee

• A.H. Piersma, Chairman Professor of Reproductive and Developmental Toxicology, Utrecht

University, Utrecht and National Institute of Public Health and the

Environment, Bilthoven

• D. Lindhout

Professor of Medical Genetics, Paediatrician (not practising), Clinical

Geneticist, University Medical Centre, Utrecht

• N. Roeleveld

Reproductive Epidemiologist, Radboud university medical centre, Nijmegen

• J.G. Theuns-van Vliet

Reproductive Toxicologist, TNO Triskelion BV, Zeist

• D.H. Waalkens-Berendsen

Reproductive Toxicologist, Zeist

• P.J.J.M. Weterings

Toxicologist, Weterings Consultancy BV, Rosmalen

• A.S.A.M. van der Burght, Scientific Secretary Health Council of the Netherlands, Den Haag

• J.T.J. Stouten, Scientific Secretary Health Council of the Netherlands, Den Haag

The first draft of this report was prepared by Dr. H.M. Barentsen, from the

Regulatory Affairs Department of WIL Research Europe BV (Den Bosch,

The Committee 31

the Netherlands) by contract with the Ministry of Social Affairs and

Employment.

The Health Council and interests

Members of Health Council Committees are appointed in a personal capacity

because of their special expertise in the matters to be addressed. Nonetheless, it

is precisely because of this expertise that they may also have interests. This in

itself does not necessarily present an obstacle for membership of a Health

Council Committee. Transparency regarding possible conflicts of interest is

nonetheless important, both for the chairperson and members of a Committee

and for the President of the Health Council. On being invited to join a

Committee, members are asked to submit a form detailing the functions they

hold and any other material and immaterial interests which could be relevant for

the Committee’s work. It is the responsibility of the President of the Health

Council to assess whether the interests indicated constitute grounds for non-

appointment. An advisorship will then sometimes make it possible to exploit the

expertise of the specialist involved. During the inaugural meeting the

declarations issued are discussed, so that all members of the Committee are

aware of each other’s possible interests.

32 Tellurium

BAnnex

The submission letter (in English)

Subject : Submission of the advisory report Tellurium

Your reference : DGV/MBO/U-932542

Our reference : U-8075/HS/cn/543-H14

Enclosed : 1

Date : April 3, 2014

Dear Minister,

I hereby submit the advisory report on the effects of tellurium on fertility and on

the development of the progeny; it also concerns effects on lactation and on the

progeny via lactation. This advisory report is part of an extensive series in which

reproduction toxic substances are classified in accordance with European

guidelines. This involves substances to which people may be exposed

occupationally.

The advisory report was prepared by a permanent committee of the Health

Council of the Netherlands, the Subcommittee on the Classification of

Reproduction Toxic Substances. The advisory report was consequently reviewed

by the Health Council’s Standing Committee on Health and the Environment.

The submission letter (in English) 33

Today I sent copies of this advisory report to the State Secretary of Infrastructure

and the Environment and to the Minister of Health, Welfare and Sport, for their

information.

Yours sincerely,

(signed)

Prof. dr. W.A. van Gool,

President

34 Tellurium

CAnnex

Comments on the public draft

A draft of the present report was released in 2013 for public review. The

following organisations and persons have commented on the draft document:

• T.J. Lentz, K. Krajnak; National Institute for Occupational Safety and Health, Cincinnati OH, USA

• K. Heitmann; UMCO Umwelt Consult GmbH, Hamburg, Germany.

The received comments, and the replies by the Committee can be found on the

website of the Health Council.

Comments on the public draft 35

36 Tellurium

DAnnex

Regulation (EC) 1272/2008 of the

European Community

3.7 Reproductive toxicity

3.7.1 Definitions and general considerations

3.7.1.1 Reproductive toxicity includes adverse effects on sexual function and fertility in adult

males and females, as well as developmental toxicity in the offspring. The definitions presented

below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Princi-

ples for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classi-

fication purposes, the known induction of genetically based heritable effects in the offspring is

addressed in Germ Cell Mutagenicity (section 3.5), since in the present classification system it is con-

sidered more appropriate to address such effects under the separate hazard class of germ cell muta-

genicity.

In this classification system, reproductive toxicity is subdivided under two main headings:

(a) adverse effects on sexual function and fertility;

(b) adverse effects on development of the offspring.

Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function

and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures con-

taining them, shall be classified as reproductive toxicants.

Regulation (EC) 1272/2008 of the European Community 37

3.7.1.2 For the purpose of classification the hazard class Reproductive Toxicity is differentiated

into:

• adverse effects

• on sexual function and fertility, or

• on development;

• effects on or via lactation.

3.7.1.3 Adverse effects on sexual function and fertility

Any effect of substances that has the potential to interfere with sexual function and fertility. This

includes, but is not limited to, alterations to the female and male reproductive system, adverse effects

on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour,

fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in

other functions that are dependent on the integrity of the reproductive systems.

3.7.1.4 Adverse effects on development of the offspring

Developmental toxicity includes, in its widest sense, any effect which interferes with normal devel-

opment of the conceptus, either before or after birth, and resulting from exposure of either parent

prior to conception, or exposure of the developing offspring during prenatal development, or postna-

tally, to the time of sexual maturation. However, it is considered that classification under the heading

of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and

for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification,

developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of

parental exposure. These effects can be manifested at any point in the life span of the organism. The

major manifestations of developmental toxicity include (1) death of the developing organism, (2)

structural abnormality, (3) altered growth, and (4) functional deficiency.

3.7.1.5 Adverse effects on or via lactation are also included in reproductive toxicity, but for

classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is

desirable to be able to classify substances specifically for an adverse effect on lactation so that a spe-

cific hazard warning about this effect can be provided for lactating mothers.

38 Tellurium

3.7.2 Classification criteria for substances

3.7.2.1 Hazard categories

3.7.2.1.1 For the purpose of classification for reproductive toxicity, substances are allocated to

one of two categories. Within each category, effects on sexual function and fertility, and on develop-

ment, are considered separately. In addition, effects on lactation are allocated to a separate hazard cat-

egory.

Table 3.7.1(a) Hazard categories for reproductive toxicants.

Categories Criteria

CATEGORY 1 Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when

they are known to have produced an adverse effect on sexual function

and fertility, or on development in humans or when there is evidence

from animal studies, possibly supplemented with other information, to

provide a strong presumption that the substance has the capacity to

interfere with reproduction in humans. The classification of a sub-

stance is further distinguished on the basis of whether the evidence for

classification is primarily from human data (Category 1A) or from

animal data (Category 1B).

Category 1A Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on

evidence from humans.

Category 1B Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on

data from animal studies. Such data shall provide clear evidence of an

adverse effect on sexual function and fertility or on development in

the absence of other toxic effects, or if occurring together with other

toxic effects the adverse effect on reproduction is considered not to be

a secondary non-specific consequence of other toxic effects. However,

when there is mechanistic information that raises doubt about the rele-

vance of the effect for humans, classification in Category 2 may be

more appropriate.

CATEGORY 2 Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when

there is some evidence from humans or experimental animals, possi-

bly supplemented with other information, of an adverse effect on sex-

ual function and fertility, or on development, and where the evidence

is not sufficiently convincing to place the substance in Category 1. If

deficiencies in the study make the quality of evidence less convincing,

Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic

effects, or if occurring together with other toxic effects the adverse

effect on reproduction is considered not to be a secondary non-specific

consequence of the other toxic effects.

Regulation (EC) 1272/2008 of the European Community 39

3.7.2.2 Basis of classification

3.7.2.2.1 Classification is made on the basis of the appropriate criteria, outlined above, and an

assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is

intended to be used for substances which have an intrinsic, specific property to produce an adverse

effect on reproduction and substances shall not be so classified if such an effect is produced solely as

a non-specific secondary consequence of other toxic effects.

The classification of a substance is derived from the hazard categories in the following order of pre-

cedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lac-

tation. If a substance meets the criteria for classification into both of the main categories (for example

Category 1B for effects on sexual function and fertility and also Category 2 for development) then

both hazard differentiations shall be communicated by the respective hazard statements. Classifica-

tion in the additional category for effects on or via lactation will be considered irrespective of a clas-

sification into Category 1A, Category 1B or Category 2.

3.7.2.2.2 In the evaluation of toxic effects on the developing offspring, it is important to consider

the possible influence of maternal toxicity (see section 3.7.2.4).

3.7.2.2.3 For human evidence to provide the primary basis for a Category 1A classification there

must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classifi-

cation shall ideally be from well conducted epidemiological studies which include the use of appro-

priate controls, balanced assessment, and due consideration of bias or confounding factors. Less

rigorous data from studies in humans shall be supplemented with adequate data from studies in

experimental animals and classification in Category 1B shall be considered.

Table 3.7.1(b) Hazard category for lactation effects.

EFFECTS ON OR VIA LACTATION

Effects on or via lactation are allocated to a separate single category. It is recognised that for many

substances there is no information on the potential to cause adverse effects on the offspring via lacta-

tion. However, substances which are absorbed by women and have been shown to interfere with lac-

tation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause

concern for the health of a breastfed child, shall be classified and labelled to indicate this property

hazardous to breastfed babies. This classification can be assigned on the:

(a) human evidence indicating a hazard to babies during the lactation period; and/or

(b) results of one or two generation studies in animals which provide clear evidence of adverse effect

in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the sub-

stance is present in potentially toxic levels in breast milk.

40 Tellurium

3.7.2.3 Weight of evidence

3.7.2.3.1 Classification as a reproductive toxicant is made on the basis of an assessment of the

total weight of evidence, see section 1.1.1. This means that all available information that bears on the

determination of reproductive toxicity is considered together, such as epidemiological studies and

case reports in humans and specific reproduction studies along with sub-chronic, chronic and special

study results in animals that provide relevant information regarding toxicity to reproductive and

related endocrine organs. Evaluation of substances chemically related to the substance under study

may also be included, particularly when information on the substance is scarce. The weight given to

the available evidence will be influenced by factors such as the quality of the studies, consistency of

results, nature and severity of effects, the presence of maternal toxicity in experimental animal stud-

ies, level of statistical significance for inter-group differences, number of endpoints affected, rele-

vance of route of administration to humans and freedom from bias. Both positive and negative results

are assembled together into a weight of evidence determination. A single, positive study performed

according to good scientific principles and with statistically or biologically significant positive results

may justify classification (see also 3.7.2.2.3).

3.7.2.3.2 Toxicokinetic studies in animals and humans, site of action and mechanism or mode of

action study results may provide relevant information which reduces or increases concerns about the

hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or

mode of action has no relevance for humans or when the toxicokinetic differences are so marked that

it is certain that the hazardous property will not be expressed in humans then a substance which pro-

duces an adverse effect on reproduction in experimental animals should not be classified.

3.7.2.3.3 If, in some reproductive toxicity studies in experimental animals the only effects

recorded are considered to be of low or minimal toxicological significance, classification may not

necessarily be the outcome. These effects include small changes in semen parameters or in the inci-

dence of spontaneous defects in the foetus, small changes in the proportions of common foetal vari-

ants such as are observed in skeletal examinations, or in foetal weights, or small differences in

postnatal developmental assessments.

3.7.2.3.4 Data from animal studies ideally shall provide clear evidence of specific reproductive

toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs

together with other toxic effects in the dam, the potential influence of the generalised adverse effects

shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the

embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely

to have influenced these effects, as part of the weight of evidence. In general, developmental effects

that are observed at maternally toxic doses shall not be automatically discounted. Discounting devel-

Regulation (EC) 1272/2008 of the European Community 41

opmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis

when a causal relationship is established or refuted.

3.7.2.3.5 If appropriate information is available it is important to try to determine whether devel-

opmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary

mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of mater-

nal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly dem-

onstrated that the effects are secondary non-specific effects. This is especially the case when the

effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In

some situations it can be assumed that reproductive toxicity is due to a secondary consequence of

maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there

is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.

3.7.2.4 Maternal toxicity

3.7.2.4.1 Development of the offspring throughout gestation and during the early postnatal stages

can be influenced by toxic effects in the mother either through non-specific mechanisms related to

stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In

the interpretation of the developmental outcome to decide classification for developmental effects it

is important to consider the possible influence of maternal toxicity. This is a complex issue because

of uncertainties surrounding the relationship between maternal toxicity and developmental outcome.

Expert judgement and a weight of evidence approach, using all available studies, shall be used to

determine the degree of influence that shall be attributed to maternal toxicity when interpreting the

criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be

first considered, and then maternal toxicity, along with any other factors which are likely to have

influenced these effects, as weight of evidence, to help reach a conclusion about classification.

3.7.2.4.2 Based on pragmatic observation, maternal toxicity may, depending on severity, influ-

ence development via non-specific secondary mechanisms, producing effects such as depressed foe-

tal weight, retarded ossification, and possibly resorptions and certain malformations in some strains

of certain species. However, the limited number of studies which have investigated the relationship

between developmental effects and general maternal toxicity have failed to demonstrate a consistent,

reproducible relationship across species. Developmental effects which occur even in the presence of

maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivo-

cally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal

toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the

offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, signifi-

cant post-natal functional deficiencies.

42 Tellurium

3.7.2.4.3 Classification shall not automatically be discounted for substances that produce devel-

opmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated

mechanism has been demonstrated. In such a case, classification in Category 2 may be considered

more appropriate than Category 1. However, when a substance is so toxic that maternal death or

severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable

to assume that developmental toxicity is produced solely as a secondary consequence of maternal

toxicity and discount the developmental effects. Classification is not necessarily the outcome in the

case of minor developmental changes, when there is only a small reduction in foetal/pup body weight

or retardation of ossification when seen in association with maternal toxicity.

3.7.2.4.4 Some of the end points used to assess maternal effects are provided below. Data on

these end points, if available, need to be evaluated in light of their statistical or biological signifi-

cance and dose response relationship.

Maternal mortality:

an increased incidence of mortality among the treated dams over the controls shall be considered evi-

dence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the

systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive

and the data for that dose level shall not normally be considered for further evaluation.

Mating index

(no. animals with seminal plugs or sperm/no. mated × 100) (*)

Fertility index

(no. animals with implants/no. of matings × 100)

Gestation length

(if allowed to deliver)

Body weight and body weight change:

Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight

shall be included in the evaluation of maternal toxicity whenever such data are available. The calcula-

* () It is recognised that the Mating index and the Fertility index can also be affected by the male.

Regulation (EC) 1272/2008 of the European Community 43

tion of an adjusted (corrected) mean maternal body weight change, which is the difference between

the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the

weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the

body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in

body weight during pregnancy.

Food and water consumption (if relevant):

The observation of a significant decrease in the average food or water consumption in treated dams

compared to the control group is useful in evaluating maternal toxicity, particularly when the test

material is administered in the diet or drinking water. Changes in food or water consumption need to

be evaluated in conjunction with maternal body weights when determining if the effects noted are

reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.

Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):

The observation of increased incidence of significant clinical signs of toxicity in treated dams relative

to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the

assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be

reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity,

loss of righting reflex, ataxia, or laboured breathing.

Post-mortem data:

Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity.

This can include gross or microscopic pathological findings or organ weight data, including absolute

organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by find-

ings of adverse histopathological effects in the affected organ(s), the observation of a significant

change in the average weight of suspected target organ(s) of treated dams, compared to those in the

control group, may be considered evidence of maternal toxicity.

3.7.2.5 Animal and experimental data

3.7.2.5.1 A number of internationally accepted test methods are available; these include methods

for developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-gen-

eration toxicity testing (e.g. OECD Test Guidelines 415, 416).

3.7.2.5.2 Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/

Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with

44 Tellurium

Reproduction/Development Toxicity Screening Test) can also be used to justify classification,

although it is recognised that the quality of this evidence is less reliable than that obtained through

full studies.

3.7.2.5.3 Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies,

which are judged likely to impair reproductive function and which occur in the absence of significant

generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the

gonads.

3.7.2.5.4 Evidence from in vitro assays, or non-mammalian tests, and from analogous substances

using structure-activity relationship (SAR), can contribute to the procedure for classification. In all

cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate

data shall not be used as a primary support for classification.

3.7.2.5.5 It is preferable that animal studies are conducted using appropriate routes of administra-

tion which relate to the potential route of human exposure. However, in practice, reproductive toxic-

ity studies are commonly conducted using the oral route, and such studies will normally be suitable

for evaluating the hazardous properties of the substance with respect to reproductive toxicity. How-

ever, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action

has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that

the hazardous property will not be expressed in humans then a substance which produces an adverse

effect on reproduction in experimental animals shall not be classified.

3.7.2.5.6 Studies involving routes of administration such as intravenous or intraperitoneal injec-

tion, which result in exposure of the reproductive organs to unrealistically high levels of the test sub-

stance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with

extreme caution and on their own are not normally the basis for classification.

3.7.2.5.7 There is general agreement about the concept of a limit dose, above which the produc-

tion of an adverse effect is considered to be outside the criteria which lead to classification, but not

regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guide-

lines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher

doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of

exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific

limit dose may not be adequate for situations where humans are more sensitive than the animal

model.

3.7.2.5.8 In principle, adverse effects on reproduction seen only at very high dose levels in animal

studies (for example doses that induce prostration, severe inappetence, excessive mortality) would

Regulation (EC) 1272/2008 of the European Community 45

not normally lead to classification, unless other information is available, e.g. toxicokinetics informa-

tion indicating that humans may be more susceptible than animals, to suggest that classification is

appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this

area.

3.7.2.5.9 However, specification of the actual ‘limit dose’ will depend upon the test method that

has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose tox-

icity studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose,

unless expected human response indicates the need for a higher dose level.

3.7.3 Classification criteria for mixtures

3.7.3.1 Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

3.7.3.1.1 The mixture shall be classified as a reproductive toxicant when at least one ingredient

has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present

at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Cat-

egory 1B and Category 2 respectively.

3.7.3.1.2 The mixture shall be classified for effects on or via lactation when at least one ingredi-

ent has been classified for effects on or via lactation and is present at or above the appropriate generic

concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.

Note The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1 If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in

the mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture upon request.

Table 3.7.2 Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or foreffects on or via

lactation that trigger classification of the mixture.

Ingredient classified as: Generic concentration limits triggering classification of a mixture as:

Category 1A reproductive toxicant

Category 1B reproductive toxicant

Category 2 reproductive toxicant

Additional category for effects on or via l actation

Category 1A reproductive toxicant

≥ 0,3 %

[Note 1]

Category 1B reproductive toxicant

≥ 0,3 %

[Note 1]

Category 2 reproductive toxicant

≥ 3,0 %

[Note 1]

Additional category for effects on or via lactation

≥ 0,3 %

[Note 1]

46 Tellurium

3.7.3.2 Classification of mixtures when data are available for the complete mixture

3.7.3.2.1 Classification of mixtures will be based on the available test data for the individual

ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-

case basis, test data on mixtures may be used for classification when demonstrating effects that have

not been established from the evaluation based on the individual components. In such cases, the test

results for the mixture as a whole must be shown to be conclusive taking into account dose and other

factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems.

Adequate documentation supporting the classification shall be retained and made available for review

upon request.

3.7.3.3 Classification of mixtures when data are not available for the complete mixture:

bridging principles

3.7.3.3.1 Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine

its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested

mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance

with the applicable bridging rules set out in section 1.1.3.

3.7.4 Hazard Communication

3.7.4.1 Label elements shall be used for substances or mixtures meeting the criteria for

classification in this hazard class in accordance with Table 3.7.3

Regulation (EC) 1272/2008 of the European Community 47

Table 3.7.3 Label elements for reproductive toxicity.

Classification Category 1A or Category 1B Category 2 Additional category

for effects on or via

lactation

GHS Pictograms No pictogram

Signal Word Danger Warning No signal word

Hazard Statement H360: May damage fertility or the

unborn child (state specific effect if

known)(state route of exposure if it is

conclusively proven that no other

routes of exposure cause the hazard)

H361: Suspected of damaging fertil-

ity or the unborn child (state specific

effect if known) (state route of expo-

sure if it is conclusively proven that

no other routes of exposure cause the

hazard)

H362: May cause

harm to breast-fed

children.

Precautionary Statement

Prevention

P201

P202

P281

P201

P202

P281

P201

P260

P263

P264

P270

Precautionary Statement

Response

P308 + P313 P308 + P313 P308 + P313

Precautionary Statement

Storage

P405 P405

Precautionary Statement

Disposal

P501 P501

48 Tellurium

EAnnex

Additional considerations to

Regulation (EC) 1272/2008

The classification and labelling of substances is performed according to the

guidelines of the European Union (Regulation (EC)1272/2008) presented in

Annex D. The classification of compounds is ultimately dependent on an

integrated assessment of the nature of all parental and developmental effects

observed, their specificity and adversity, and the dosages at which the various

effects occur. The guideline necessarily leaves room for interpretation, dependent

on the specific data set under consideration. In the process of using the

regulation, the Committee has agreed upon a number of additional

considerations:

• if there is sufficient evidence to establish a causal relationship between

human exposure to the substance and impaired fertility or subsequent

developmental toxic effects in the offspring, the compound will be classified

in category 1A, irrespective of the general toxic effects (see Annex D,

3.7.2.2.1.)

• adverse effects in a reproductive study, occurring without reporting the

parental or maternal toxicity, may lead to a classification other than category

1B, when the effects occur at dose levels which cause severe toxicity in

general toxicity studies

• clear adverse reproductive effects will not be disregarded on the basis of

reversibility per se

Additional considerations to Regulation (EC) 1272/2008 49

• the Committee dot not only use guideline studies (studies performed

according to OECD* standard protocols) for the classification of compounds,

but non-guideline studies are taken into consideration as well.

* Organisation for Economic Cooperation and Development.

50 Tellurium

FAnnex

Developmental toxicity studies

Table 1 Developmental toxicity studies with tellurium in animals.

authors species experimental period/design

dose/route general

toxicity

developmental toxicity

Garro/

Pentschew

(1964)

Long-Evans

rats(n>100)

low/mid dose:

throughout gestation;

high dose: throughout

gestation until 3-5 d

before expected

delivery

0, 500, 1,250,

2,500 ppm

(ca. 30, 75,

150 mg/kg

bw/da); diet

not toxic to

dams: dams

tolerated diets

well; behaved

normally

pups appeared normal although smaller

than controls

hydrocephalus developed immediately

after birth; incidences:

500 ppm: unspecified increase

1,250 ppm: 60-90%

2,500 ppm: 99%

mortality: 99% of all affected pups within 1 mo

Agnew et al.

(1968)

Wistar rats

(n=4 low/mid

dose; n=10

high dose)

throughout gestation 0, 1,250,

2,500, 3,300

ppm (ca. 75,

150, 200 mg/

kg bw/da); diet

not reported 1,250 ppm: no hydrocephalus

500 ppm; no hydrocephalus

3,300 ppm: hydrocephalus in 8/10 litters

(allowed to live ≥19 d; appearing grossly

after pnd 4 or 5) and in 36/77 pups

Duckett (1970) Wistar rats

(n=20)

daily throughout

gestation;

examination of foetal

brains on gd 13, 15;

only foetuses of

tellurium-fed animals,

eventually giving

birth to hydrocephalic

animals,and foetuses

of similar age from

the control rats

3,000 ppm

(ca. 45 mg/rat

or 180 mg/kg

bw/d); diet

not reported no effect on size and appearance of

foetuses; no anomalies in sections of the

brains of the tellurium foetuses, stained

with haematoxylin-eosin; electron

microscopic examination: morphological

anomalies in cells of ependymal layer:

ependymal layer of normal foetal rat

resembled that of human, rabbit, and

chick foetuses; on the ventricular surface

of the ependymal cells from tellurium

foetuses. normally

Developmental toxicity studies 51

examined and

reported

present microvilli not present and

number of mitochondria greatly

diminished; mitochondria often

abnormal, smaller and darker than

normal and showed distortion of cristae;

cells in the rest of the telencephalon

appeared to be normal

Duckett et al.

(1971)

rats (strain not

specified)

(n=20)

daily throughout

gestation; on gd 1-9,

10-15, 16-21; (exact

day of examination

not reported)

2,500 ppm

(ca. 150 mg/

kg bw/d); diet

not reported 12 rats fed during gd 10-15 gave birth to

hydrocephalic rats (average litter 9 with

5 hydrocephalic); no hydrocephalic

animals during other dosing periods

Duckett et al.

(1971)

rats (strain not

specified)

(n=5)

one of gd 1-21;

number of postnatal

hydrocephalus (exact

day of examination

not reported)

2,500 ppm

(ca. 150 mg/

kg bw/d); diet

3 animals died

(not further

specified)

72 animals gave birth to an average of 8

offspring; no hydrocephalic animals; no

further information

Agnew/Curry

(1972)

Long-Evans

rats (n=5-10;

controls 2-3)

one of gd 7-13;

sacrifice: pnd 10

examined for

hydrocephalus and

other visceral effects;

only mothers failing

to deliver were

autopsied and

examined for foetal

resorptions the day

following predicted

delivery

0, 13 mg/kg

bw

(suspended in

olive oil); im

not reported after injection on gd 8: delivery in 5/8

after injection on gd 7, 8, 10, 11: total

number of offspring/group rather low,

number of foetal resorptions increased;

after injection on gd 7, 9, 10: number of

foetuses with hydrocephalus: 1, 14, 10,

resp. (vs. 1 in controls); no other

malformations observed

Johnson et al.

(1988)

Sprague-

Dawley rats;

(n=32-33)

gd 6-15; sacrifice: 2/3

on gd 20: foetuses

examined; 1/3 allowed

to deliver: pups

observed until pnd 7;

pup heads (stillborn,

found dead or killed)

examined

0, 30, 300,

3,000, 15,000

ppm (ca. 0, 2,

20, 166, 633

mg/kg bw/d

for gd 6-10; 0,

2, 18, 173,

580 mg/kg

bw/d for gd

11-15); diet

no mortality;

300, 3,000,

15,000 ppm:

decreased

maternal

weight gain,

food

consumption

(during

exposure;

p≤0.01 at gd

6-9, gd 6-15);

3,000, 15,000

ppm: thin

appearance);

not clear at

which levels:

preparturi-

tional vaginal

bleeding,

decreased

motor activity

foetuses: no effect on incidence of

pregnancy, mean number of corpora

lutea, implantations, live and dead

foetuses, resorptions, litter size, % of

males;

15,000 ppm: decreased weights of male,

females (p≤0.05); % litters with

variations: 100% (controls: 18%;

p≤0.01); % foetuses with variations: 41%

(controls: 2.1%; p-value not presented);

increased incidence of malformed

foetuses (no details), of foetuses with

delayed ossification (no details); most

common malformation: internal

hydrocephalus with dilatation of the

lateral ventricles: in 17 litters (85%) vs. 1

in controls (4.6%) (p≤0.05); in 67

foetuses (55%) vs. 1 in controls (0.7%)

(p≤0.05); also slight to marked dilatation

of the third and/or fourth ventricles in

more severely affected foetuses;

externally hydrocephalus in 2 foetuses

(one had enlarged fontanelle bordered by

52 Tellurium

a haemorrhagic area); dilatation of renal

pelvis (no details); other malformations

(no further details): kinked and/or

stubbed tails, rotation of hind limb/foot,

malformed retina, malpositioned

manubrium and clavicles, short radius,

ulna and/or femur, wavy ribs, thickened/

split rib; delayed ossification of the

parietals, interparietals, supraoccipitals,

vertebral and sternal centra, pubes,

ischia, and/or ribs in many of these

foetuses from severely affected dams

3000 ppm; % litters with variations:

57% ( p≤0.05); % foetuses with

variations: 11% (p-value not presented);

increased incidence of malformed

foetuses (no details), of foetuses with

delayed ossification (no details); most

common malformation: internal

hydrocephalus with dilatation of the

lateral ventricles: in 3 litters (14%) (n.s.);

in 11 foetuses (8.3%) (n.s.); dilatation of

renal pelvis (no details); no other

malformations treatment had no effect on

duration of gestation in groups allowed

to litter; pups: no effect on number of

dams with stillbirths, litter size, of live

pups delivered, on mean pup weights at

pnd 7 15,000 ppm; decreased number

(%) of pups surviving 7 d (p≤0.01); % of

litters with dilated lateral ventricles at

pnd 7: 75% (controls:0) ((p≤0.01); % of

pups with dilated lateral ventricles at pnd

7: 61% (controls:0) ((p≤0.01); no (other)

gross, external or visceral anomalies

Johnson et al.

(1988)

New Zealand

white rabbits

(n=17)

gd 6-18; sacrifice: gd

29

0, 17.5, 175,

1,750, 5,250

ppm (ca. 0,

0.8, 8, 52, 97

mg/kg bw/d

using feed

intake gd 6-18

and maternal

bw on gd 6);

diet

1,750, 5,250

ppm:

decreased bw

gain (p≤0.01),

food

consumption

(p≤0.05,

p≤0.01, resp.),

soft or liquid

faeces,

alopecia, thin

appearance,

and/or

decreased

motor activity

(p≤0.01)

5,250

number of pregnancies varied between

dose levels: 10, 15, 9, 15 and 13 at 0,

17.5, 175, 1750 or 5250 ppm,

respectively;

no effect on incidences of abortion, mean

numbers of corpora lutea, implantations,

resorptions, litter size, on % male

foetuses/litter;

5250 ppm: decreased foetal weight:

males 84%, females 95% of controls;

incidence of litters with abnormalities:

46% (controls: 2%); of foetuses with

abnormalities: 12% (controls: 6.7%);

increased in malformed foetuses (no

details), foetuses with delayed

ossification (no details); low incidences

of hydrocephalus; enlarged and/or

Developmental toxicity studies 53

abbreviations: bw=body weight; d=day(s); gd=gestational day(s); im=intramuscular; mo=month(s); pnd=postnatal day(s).

ppm: adverse

clinical signs

(not further

specified)

(p≤0.01)

irregularly shaped anterior fontanelle;

incomplete ossification of, or small holes

in, the frontals and parietals; frontals

with thickened ossification; umbilical

hernia; fused pulmonary artery, aorta;

asymmetric and/or irregularly shaped

and/or fused sternebrae; thickenedareas

in ribs; foetuses also tended to be smaller

than normal with fewer caudal vertebral,

xiphoid, forepaw phalangeal ossification

sites

a based on the data of Duckett (1970) and Johnson et al. (1988)

54 Tellurium

Advisory Reports

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Tellurium2014/07

TelluriumContentsSamenvattingExecutive summaryScope1.1 Background1.2 Committee and procedure1.3 Labelling for lactation1.4 Data1.5 Presentation of conclusions1.6 Final remark

Tellurium2.1 Introduction2.2 Human studies2.3 Animal studies2.4 Conclusions

ReferencesThe CommitteeThe submission letter (in English)Comments on the public draftRegulation (EC) 1272/2008 of the European CommunityAdditional considerations to Regulation (EC) 1272/2008Developmental toxicity studies